Abstract The prevalence of Alzheimer?s disease (AD) and related dementias (ADRD) has been increasing over the past few decades and is projected to double by 2025 and triple by 2050. AD is still incurable, and causes of ADRD remain largely unknown, but they have been linked to many risk factors, including age, education, history of psychiatric disorders, head trauma, and vascular diseases or related risk factors. More recently, antihypertensive and antidiabetic drug therapies have been associated with a lower risk of developing dementia and early cognitive impairment. In 2019, a large clinical trial reported that intensive blood pressure control significantly reduced the risk of mild cognitive impairment and was the first trial to demonstrate an effective strategy for the prevention of age-related cognitive impairment. Given a high prevalence of hypertension and diabetes in the adult population, the utilization of disease-modifying drugs may provide an effective strategy for the prevention of ADRD. However, there is no large cohort study monitoring and assessing the joint effects of antihypertensive, antidiabetic, and anticancer medications on the risk of ADRD. Medicare, which has covered a large population aged 65 or older in the U.S. since 1965 with comprehensive and well-documented electronic databases available since 1991 (including anticancer chemotherapy), provides a great opportunity and resource to monitor the prevalence and incidence of ADRD over time. In addition, since Medicare Part-D comprehensive drug coverage was implemented in 2006, it is possible to determine the impact of antihypertensive and antidiabetic drugs on the risk of these dementias. Hence, the primary goal of this proposed study is to test the hypothesis that anticancer, antihypertensive and antidiabetic drug therapies have impacted the prevalence and incidence of ADRD over the past 30 years. To accomplish this, we propose to address the following Specific Aims: 1) to determine the secular trends in the prevalence of ADRD from 1991 to 2020 among Medicare beneficiaries aged 65 or older in the United States and variations in the prevalence of ADRD by state, geographic region, age, gender, race/ethnicity, and comorbidity; 2) to determine the incidence of developing ADRD in association with vascular factors and other potential risk factors among Medicare beneficiaries who were free of dementia at baseline and followed for up to 30 years; 3) to determine the association between a cancer diagnosis and anticancer drug therapies and the risk of developing ADRD by comparing a large cohort of patients diagnosed with major cancers to those with similar background risks but without cancer in 1991-2020; and 4) to determine the independent and joint effects of antihypertensive, antidiabetic and anticancer drug therapies on the risk of developing ADRD among Medicare beneficiaries aged 65 or older in 2007-2020 after Medicare Part-D comprehensive drug data became available. The findings from this study will have significant implications for preventing or delaying the onset of ADRD and hence will make substantial contributions to the primary research goal of the National Alzheimer?s Project Act by 2025.